1. Field of the Invention
This invention pertains to methods of treating cancer, and more particularly methods of reducing colony number using novel benzothiazole compounds in association with IL-2 (interleukin-2) activated natural killer (A-NK) cells and interleukin-2.
2. Description of Related Art
In the recent years there has been an ever increasing interest in the development and application of technologies for the treatment of cancer. However, the successful treatment of advanced cancer, i.e. cancer metastases has been mostly elusive.
It is recognized that patients with newly diagnosed solid malignancies already have occult, secondary metastatic tumors in distant organs. At least 50% of these metastases are resistant to conventional anti-cancer treatments of radiotherapy, chemotherapy or surgery and the majority of morbidity and mortality of patients with solid malignancies is great. This is directly related to the inability thus far to effectively treat cancer metastases.
According to Goldfarb and Whiteside, Tumor Immunology and Cancer Therapy, Pittsburgh Cancer Institute, Marcel Dekker, Inc. (1994), adoptive immunotherapy with interleukin-2 (IL-2) and lymphokine activated killer (LAK) cells or plastic adherence-enriched LAK (A-NK also known as A-LAK) cells has produced reductions in the number of metastatic lesions in several animal systems. In clinical settings, LAK cell therapy has also been at least successful in part, with complete or partial responses in 20-30% of the patients with advanced cancer, especially malignant melanoma and renal cell carcinoma. However, although adoptively transferred A-NK cells have the ability to find and infiltrate malignant lesions in a time dependent fashion, it is nonetheless a very inefficient process. Nevertheless, frequent long-term survival and complete eradication of metastases, has not yet been achieved, indicating the need for improvement of this therapeutic modality.
In a study by Basse et al., Tissue Distribution of Adoptively Transferred Adherent LAK Cells: Role of the Route of Administration, Nat. Immun. 11:193-202 (1992) it was reported that adoptive immunotherapy, in combination with IL-2 showed numerical reduction in the number of experimental metastases. However, it was also reported that complete remissions are seldom seen and that there is an urgent need to design new approaches to enhance the frequency and duration of the therapeutic responses.
Furthermore, according to Goldfarb, et al. Preclinical studies of IL-2 Activated Natural Killer Effector Cells for Locoregional Therapy of Metastatic Cancer, Journal of Infusional Chemotherapy, Vol. 4, No. 2 (1994), it was determined that IL-2 did not have a direct effect on cancer cells but mediated its antitumor activity by altering host immune responses, suggesting that immunologic therapy of cancer can be effective in selected patients with metastatic cancer. However, it was found that eradication of metastases with long-term survival has not been routinely achieved through this avenue.
There have been other approaches studied for treating cancer. One such approach is to transfect A-NK cells with genes for cytotoxic molecules to selectively target them to metastatic sites. However Goldfarb, Natural Killer Cells and Gene Therapy: Potential of Gene Transfection for Optimizing Effector Cell Functions and for Targeting Gene Products into Tumor Metastases, Nat Immun 13:131-140 (1994) indicated that additional knowledge is required concerning the potential role of specific cytokines in vivo for the therapy of established tumors.
Therefore, there is a present and urgent need for an anticancer agent that is more effective against highly invasive, advanced metastatic tumors which are resistant to conventional anti-cancer drugs. It is thus, an object of the present invention to provide an anticancer agent that is highly effective against very invasive, advanced metastatic tumors and that resolves the problems experienced with anticancer agents of the past. It is an object of the present invention to provide a method of treatment that reduces colony number.